1. Field of the Invention
The present invention relates to inhibition by short interference RNA (hereinafter, referred to as siRNA in some cases) of expression of the nuclear receptor CAR that acts on transcriptional control of drug-metabolizing enzymes.
2. Description of the Related Art
Constitutive Active/Androstane Receptor (CAR) is a transcription factor belonging to the nuclear receptor family and plays a role of biological defense mechanism against is increase in drug level in a living body. In general, it is considered that CAR induces expression of drug-metabolizing enzymes in organs such as liver and enhances the metabolism of the drug to defend the body against the administered drug (Swales and Negishi, 2004, Mol. Endo. 18(7) 1589-1598).
On the other hand, it has been reported that such a defensive mechanism of CAR causes serious side effects in mice. For example, expression level of drug-metabolizing enzymes in the liver is increased by prolonged administration of phenobarbital, and further the increase in frequency of DNA replication and reduction in apoptosis via p53, i.e., tumor suppressor gene are observed. As a result, tumorigenic transformation of the liver is induced. It has been shown that the tumorigenic transformation mechanism functions via CAR (Yamamoto et al., 2004, Cancer Res., 64, 7197-7200). Knockout animals such as CAR knockout mice have been used to examine the relationship between tumorigenic transformation by increased expression of CAR-related drug-metabolizing enzymes and toxicity of a compound like phenobarbital in animals such as mice (Yamamoto et al 2004 Cancer Res 64 7197-7200).